Memorandum

JDRF/Gubra partner on glucose-responsive insulin – June 18, 2018

Executive Highlights

  • JDRF and Gubra today announced a one-year partnership to develop a new glucose-responsive insulin (GRI). JDRF’s financial investment is undisclosed. Notably, the organization has awarded funding to several GRI development projects, including Dr. Zhen Gu’s (UNC) smart insulin patch. This latest investment from JDRF is certainly a vote of confidence in Gubra.

  • As we learned from Gubra representatives, the company will also be contributing funds to the next stage of development, focused on refining the candidate’s glucose-sensitivity range to enable in vivo proof-of-concept clamp studies in model organisms. Gubra expects its GRI to reach the clinical stage in two-three years and anticipates that it would partner for clinical development.

  • Gubra’s GRI uses a novel mechanism: A glucose-sensitive linker is introduced at the lipidation site of human insulin, allowing for the combination of both basal and prandial insulin properties. The GRI will function as a circulating depot. Gubra is currently targeting once-daily dosing.

  • According to our records, only two glucose-responsive insulin compounds have ever reached clinical development. Merck’s MK-2640 was discontinued from phase 1 due to efficacy concerns. The same company now apparently has another GRI in phase 1 (per Dr. J Hans DeVries’ remarks at IDF). To be sure, GRI presents a variety of technical challenges and remains early-stage across the board. That said, it also holds tremendous promise in both type 1 and type 2 diabetes. In our observation, many consider GRI the next big innovation in insulin, and some would even consider it a functional type 1 “cure,” as GRI promises lower treatment burden, less hypoglycemia risk, and less long-term complication risk through better postprandial and overall glucose control.

This morning, JDRF and Gubra announced a partnership to develop a new glucose-responsive insulin (GRI). Gubra’s preclinical candidate utilizes a novel mechanistic approach, distinct from other GRIs in development: The properties of long-acting basal and fast-acting prandial insulin are combined in a single molecule, which functions as a circulating depot. Gubra is currently targeting a once-daily injection, though a once-weekly injection may also be possible. 

No details were disclosed on how much JDRF has invested, and Gubra shared with us that they are co-funding this stage of development. Notably, this is one of many GRI projects that JDRF is funding, as the organization has also given financial support to Dr. Zhen Gu at UNC, to MIT/University of Utah (Dr. Danny Chou), to Dr. Alborz Mahdavi at Protomer, and to Dr. Christoph Hagemeyer at Monash University for glucose-responsive insulin development.

Regardless of the exact investment amount, it’s certainly a vote of confidence to see JDRF invest in another GRI, and Gubra noted that the funding from JDRF will enable three- to four-fold acceleration in development. Overall, we would certainly be glad to see development speed up in this field considering the potential glucose-responsive insulin holds in both type 1 and type 2 diabetes – that said, we’re also acutely aware of the technical challenges here, and we note that all GRI candidates remain very early-stage.

The JDRF/Gubra agreement is described as an initial one-year partnership. According to Gubra, the company has been working on GRIs for the past two-three years, with heightened focus in the last year. The goal of this one-year partnership is to move the candidate’s chemistry toward in vivo proof-of-concept clamp studies in model organisms by refining the glucose-sensitivity range of the molecule. Gubra expects the candidate to reach IND/clinical stage in two-three more years.

Further down the line, Gubra says, it would expect to partner this GRI for clinical development. While the company’s preclinical contract research organization (CRO) work, especially in diabetes, could be a big advantage for the company in preclinical development, Gubra remains a business-to-business company and does not anticipate entering the clinical stage alone.

In our observation, many people in the diabetes field view GRI as the next major innovation in insulin. JDRF has a longstanding interest in this sort of technology, sponsoring a day-long workshop on the topic in 2016. Indeed, some even view GRI as a functional yet non-invasive cure for type 1 diabetes. At the very least, GRI could offer significant improvements in safety, hassle, and complexity over current insulin analogs by reducing hypoglycemia risk, postprandial glucose excursions, and injection burden.Interestingly, Gubra’s work includes preclinical CRO services in addition to drug discovery focused on metabolic disease, which could accelerate the timeline for the company’s GRI and other candidates. Last November, the company announced a partnership with BI to develop novel obesity treatments with a specific focus on regulating food intake.

Gubra’s GRI Molecule

  • Gubra described its preclinical candidate as conceptually novel within the GRI field. The molecule is built with human insulin and includes a glucose-sensitive linker introduced at the lipidation site of the insulin protein, which allows for the combination of long- and short-acting insulin properties. Functionally, when glucose is above range, insulin is freed from the lipidated and albumin-bound depot. Moreover, this GRI will function as a circulating depot, allowing for more rapid utilization of insulin when glucose rises. We’ll be curious to see how the combination of bolus and prandial insulin properties plays out in vivo; we can imagine this strategy could present challenges in balancing bolus and prandial action, but it could also offer advantages in stability and overall glucose control.

Competitive Landscape

  • Our glucose-responsive insulin landscape includes 10 other active candidates; we’ve noticed particular buzz around Dr. Gu’s work on a smart insulin patch. To our knowledge, only two GRI candidates have made it into clinical development to-date: (i) Merck’s MK-2640 was discontinued over efficacy concerns following a phase 1 study. (ii) According to Dr. J Hans DeVries’ IDF talk, Merck has advanced another GRI into phase 1 with data expected in 2018 (presumably, this unnamed candidate which showed preclinical efficacy in an ADA 2017 poster). While it’s difficult to assess such an early class of potential therapies, we do see enormous potential in both type 1 and type 2 diabetes for a glucose-responsive insulin to reduce treatment burden and lower risk of both hypoglycemia and long-term complications. That said, we are reminded that so many people struggle to afford current insulins, and innovation should of course occur alongside improved access and affordability.

 

-- by Ann Carracher, Payal Marathe, and Kelly Close